Synthesis of Nitro Compounds Using Various Nitrating Agents
Nitration involves the introduction of a nitro group (NO2) into an organic compound [1]. This procedure is often performed on the electron-rich benzene molecule or other aryl compounds. However, nitrations can also be done on simple aliphatic compounds as well. While the importance of nitro compounds may often be neglected, the nitro group serves as an important precursor in a number of organic syntheses. Functionalization of the nitro group lies in the fact that it can be converted into a number of different functional groups. For example, the nitro group can easily be reduced to the corresponding amines. They can also be converted into aldehydes or ketones via the Nef reaction. Furthermore, they can serve as a precursor to oximes, hydroxylamines, and a number of other nitrogen derivatives [2]. Today, nitrations are most notably known for the production of explosives such as trinitrotoluene (TNT) and nitroguanidine [1].
Aromatic Nitration
In organic synthesis, nitrations are oftentimes performed on aromatic compounds. The nitration of benzene was among the first to be reported by Mitscherlich in 1834. He prepared nitrobenzene by treating benzene with fuming nitric acid. Not long after, in 1845, Hofmann and Dale reported on their pioneering work involving the nitration of benzene to give mono- and dinitrobenzenes; a reagent system consisting of nitric and sulfuric acids (‘mixed acid’) was employed. The nitronium ion (NO2+) is considered the active species in the system. In a typical system consisting of nitric and sulfuric acids, the overall equation is HNO3 +2H2SO4 ↔ NO2+ + H3O+ + 2HSO4- [3].
Figure 1. Typical scheme for aromatic nitration [3].
Aromatic nitration involves the electrophilic substitution of one or more nitro groups into an aromatic ring. Because the introduction of a nitro group deactivates the ring to further electrophilic substitution, dinitrations usually require much more vigorous conditions compared to its mononitration counterpart. In addition, dinitrations are usually performed on isolated mononitrated compounds rather than stepwise reactions in situ. Notably, the nitration reaction is always strongly exothermic; for the mononitration of benzene ΔH = -117 kJ/mol and for naphthalene ΔH = -209 kJ/mol [3].
Nitryl chloride, which can easily be prepared from nitric acid and chlorosulfonic acid, has also been used as a nitrating agent for some typical aromatic compounds. Its activity can be catalyzed by acids such as hydrogen fluoride, aluminum chloride, and boron fluoride. However, it was found only to be useful on aromatics of intermediate reactivity. Highly reactive aromatics (e.g. phenol, anisole, dimethylaniline, and naphthalene) are prone to oxidative degradation, while nitryl chloride was found to be an ineffective nitrating agent for deactivated aromatics (e.g. nitrobenzene, benzoic acid, and benzaldehyde) [4].
Nitronium trifluoromethanesulfonate (triflate), NO2+ CF3SO3-, derived from nitric acid and trifluoromethanesulfonic acid, was found to be an effective nitrating reagent for aromatic nitration in inert organic solvents. Furthermore, mono- or dinitration could be made to occur by altering the reaction conditions [5]. The nitronium triflate nitrating agent can also be generated in situ from tetramethylammonium nitrate and trifluoromethanesulfonic anhydride in dichloromethane. The ionic tetramethylammonium triflate salt and triflic acid byproducts can easily be removed via a simple aqueous workup. The resulting mononitrated product was obtained in high isolated yield and purity. Dinitrated products were also observed for particular electron rich aromatic substrates. While heterocyclic aromatic rings are less susceptible to electrophilic substitution, this procedure was found to be effective for nitrating heteroaromatic compounds as well. It was observed that increasing the number of equivalents of nitronium triflate can drive the reactions to completion [6].
The boron trifluoride-dinitrogen tetroxide complex has also been studied as a nitrating agent. The solid, stable complex was found to be an excellent nitrating agent for aromatic compounds. Dinitrogen tetroxide can be dissociated homolytically or heterolytically in several different ways. In the acid promoted dissociation of N2O4, BF3 cleaves N2O4 heterolytically into NO2- and NO2+. Thus, the structure of the BF3∙N2O4 complex was formulated to be (F3B <-- NO2)- (NO2)+. It was found that this reagent system favors ortho substitution relative to para substitution. However, nitrosation rather than nitration was observed to occur on some compounds. This may be due in part to the destruction of the complex owing to the basicity of the reactants. The reactant may have been basic enough to remove BF3 from the weakly basic N2O4 and prompt the base promoted dissociation of N2O4 into NO3- and NO+, the nitrosating ion. Thus, the BF3∙N2O4 complex may induce nitrosation rather than nitration in even weakly basic materials, such as aniline and some phenols [7].
Besides electrophilic substitution, nitration of aromatic compounds can also proceed via free-radical nitration. Both hydroxylation and nitration was found to occur in the reaction between pernitrous acid and a number of simple aromatic compounds. The products formed are mainly m-nitrocompounds or o- and p-hydroxy-compounds. The homolytic fission of pernitrous acid releases hydroxyl radicals which attack the aromatic compound producing a free aryl radical. Nitration then occurs due to nitrogen dioxide (NO2) reacting with the free aryl radicals present in the solution. It was found that hydroxylation occurs almost exclusively ortho and para to the original substituent, while nitration typically occurs meta to the original substituent [8].
The nitration of aromatic carbonyl compounds such as acetophenone, benzophenone, and other ketones results in mainly meta-nitro compounds as opposed to ortho- and para-nitro derivatives. This is due to the meta-directing power of the carbonyl serving as an activating group. In a kinetic study of the nitration of acetophenone with nitric acid, it was found that highly acidic nitrating systems offered a predominant ortho/meta directionality and considerable increase in meta-substitution. As the concentration of sulfuric acid was increased from 80% to 98% at 25°C, the ratio of ortho to meta products decreased from 0.37 to 0.25. This can be explained by the increasing contribution of the conjugate acid of acetophenone due to its protonation at high acidities, thereby enhancing its meta-directing power [9].
When aromatic ketones were treated with nitrogen dioxide (NO2) in the presence of ozone, an enhanced ortho to meta ratio was observed. The ring underwent easy nitration to give ortho- and meta-nitrated products in good yields with no observable attack on the alkyl portion of the ketone. In fact, nitration did not occur in the absence of ozone. Ortho-substitution is greatly enhanced under these conditions with ratios of ortho to meta nitrated products generally ranging from 1.1-3.8 to 1.0. The amount of para-substituted products was comparably lower or undetectable in some instances. It was found that the proportion of ortho-substituted products increased as the steric bulkiness of the side chain increased. This was also accompanied by an increase in para-substitution. When the number of substituted halogen atoms on the acetyl group of acetophenone was increased, the formation of products switched from predominantly ortho to predominantly meta and finally exclusively meta [10].
Iron has been used as a catalyst for the nitration of aromatic compounds using N2O5. The ferric acetylacetonate coordination complex Fe(acac)3 serves as a good catalyst to enhance the rate of nitration under milder conditions. As exemplified by the mononitration of the mildly activated compound toluene, the nitration reaction occurred readily at -100°C in the presence of iron, while an elevated temperature of 0°C was necessary for the reaction to proceed in the absence of the iron catalyst. The N2O5/Fe(acac)3 reagent system allows for the nitration to be performed under such low temperatures. This is particularly useful for the nitration of compounds containing functional groups that are themselves vulnerable to nitration. Furthermore, quantitative yields were obtained under much shorter reaction times, typically less than four minutes. The reaction conditions were also much milder as demonstrated by the nitration of benzaldehyde to form nitrobenzaldehyde without oxidation of the aldehyde group. Unfortunately, the exact structure of the active nitrating complex and mechanism of nitration is not fully understood. Attempts to isolate the complex have also been deemed unsuccessful. It was found that after filtering and washing the complex with dichloromethane, it failed to nitrate aromatic rings stoichiometrically. However, when additional amounts of N2O5 were added, the reaction proceeded normally. Interestingly, if the complex was not formed prior to the addition of the substrate, the reaction was significantly slower and mirrors that of a reaction performed in the absence of iron [11].
Cross-linked poly(4-vinylpyridine) supported sodium nitrite, [P4-Me] NO2, in the presence of KHSO4 is a useful polymer supported nitrating reagent for the nitration of aromatic compounds. While the reaction was found to be effective for activated aromatic compounds (e.g. phenol, catechol, hydroquinone, beta-naphthol, and N,N-dimethyl aniline), the reaction was unsuccessful for the nitration of less activated aromatic compounds (e.g. biphenyl, m-xylene, and toluene) [12].
A more recent method of aromatic nitration involves the use of guanidinium nitrate as the nitrating agent. Guanidinium nitrate in 85% sulfuric acid serves as a good reagent for the nitration of a number of different aromatic compounds, including those bearing activating and deactivating groups as well as anilines and heteroaromatic compounds. Guanidinium nitrate is converted into nitroguanidine in the presence of sulfuric acid, which can then be used to generate the nitronium ion. This procedure is especially useful for selective mononitrations, due to the absence of di-nitrated and poly-nitrated products. This process was also found to be regioselective. p-substituted nitro compounds were obtained regioselectively from monosubstituted aromatic substrates except toluene. The nitration of aniline and m-substituted anilines resulted in the formation of p-nitroanilines, whereas the nitration of o- and p-substituted anilines resulted in the formation of m-nitroanilines. Surprisingly, no nitration took place at the o-position [13].
Figure 2. Aromatic nitration using guanidinium nitrate [13].
Aliphatic Nitration
Aliphatic nitro compounds can be synthesized via the nucleophilic substitution reaction of alkyl halides. Primary alkyl halides can be converted into the corresponding nitro alkanes via a reaction with silver nitrite. Excellent yields were obtained for primary, straight chain alkyl bromides and iodides. However, primary alkyl chlorides were completely unreactive. Branching on the α-carbon drastically decreased the reactivity and amount of product formed, whereas branching on the β-carbon did not seem to affect the yields much. Secondary halides are expected to produce yields of approximately 15% and tertiary halides only 0 to 5% [14]. Milder conditions performed at room temperature using four equivalents of silver nitrite under aqueous medium have also been found to be effective for the production of primary nitroalkanes from primary alkyl halides. The use of four equivalents of silver nitrate creates the necessary conditions to minimize the formation of the corresponding alcohol. This method works well on alkyl bromides and alkyl iodides, while preserving other functionalities under these milder conditions. The formation of alkyl nitrites as byproducts is also greatly reduced. Unfortunately, this method was found to be ineffective on secondary halo derivatives [15].
Nitroalkanes can be produced via the nitration of alkyl halides with metal nitrites. In the Victor-Meyer reaction, silver nitrite in diethyl ether is employed [16], while in the Kornblum reaction, sodium nitrite in N,N-dimethylformamide (DMF) [17] or dimethyl sulfoxide (DMSO) [18] is used. A slightly modified version of the Victor-Meyer reaction provided primary nitroalkanes of high purity in good yields. Lower reaction temperatures (45-55°C) were employed, as well as the use of petroleum ether as the solvent [16]. The main advantage of the Kornblum reaction over the Victor-Meyer reaction is its effectiveness on secondary halides. The use of DMF greatly enhances the solubility of sodium nitrite. Addition of a small amount of urea to DMF further enhances the solubility of sodium nitrite, making it an effective nitrating agent for even secondary alkyl halides and halogenated cyclic hydrocarbons. The reaction of alkali nitrites with alkyl halides is also appreciably faster in this medium, which minimizes the formation of competing side products. While alkyl iodides and alkyl bromides are useful in the synthesis of nitroalkanes, alkyl chlorides react too slowly to be useful [17]. DMSO proves to be an even better solvent for the nitration reaction due to the higher solubility of sodium nitrite in DMSO than DMF. This presents the possibility of more concentrated mixtures and effectively shorter reaction times. However, open chain secondary alkyl bromides seemed to give slightly higher yields in DMF. The two solvents also provided approximately the same yields for secondary alkyl iodides [18].
Dinitrogen pentoxide (N2O5) can be used as a nitrating reagent for the conversion of an amine to the corresponding nitramine. It has been found to be effective on a number of aromatic amines as well as secondary aliphatic amines. However, this reagent system was ineffective for primary amines, as N2O5 causes the acid-catalyzed decomposition of primary nitramines [19]. Nitrogen tetroxide (N2O4) has also been studied as a nitrating agent. It was found that nitrogen tetroxide can react either as a nitrosating agent or as a nitrating agent. Nitrosation was prevalent under most conditions, while nitration was found to occur only at low temperatures and only with reactants that are strong bases [20].
Figure 3. The two isomeric forms of nitrogen tetroxide [20].
This is due to the equilibrium that is established between the two isomeric forms of nitrogen tetroxide. The displacement of the nitrite ion from I leads to nitration, while the displacement of the nitrate ion from II leads to nitrosation [20].
Acetyl nitrate serves as a rapid and effective nitrating agent for many alkenes. This nitrating agent is easily obtained from the reaction of 70% nitric acid with excess acetic anhydride. While nitric acid in acetic acid has also been used as a nitrating agent, nitric acid in acetic anhydride has been shown to be a much more effective nitrating agent. Alkenes typically undergo an addition reaction withAcO-NO2 in a Markovnikov orientation to form β-nitro acetates. Smaller amounts of β-nitroalkenes and β-nitro nitrates are also obtained. The β-nitro acetates can be easily separated from the higher boiling β-nitroalkenes and β-nitro nitrates via distillation. RCH2CH2CH=CH2 (e.g. 1-butene) and R2CHCH2CH=CH2 (e.g. 3-methyl-1-butene) type alkenes were found to be relatively unreactive, producing low yields of β-nitro nitrates and β-nitro acetates in approximately equal proportions. A small amount of sulfuric acid was found to be remarkably effective at promoting the nitration of otherwise unreactive alkenes, such as 2-chloro-2-methylpropene. Overall yields were found to increase as the ratio of nitrating agent to alkene was increased from 1 to 2. This shows that the amount of nitrating agent is less than the moles of nitric acid used. Time and temperature did not seem to appreciably affect the total yield or ratio of products. Most of the reactions were essentially “complete” within five minutes. The proportion of β-nitro nitrate product was much greater for cyclic hydrocarbon compounds, (e.g. cyclopentene and cyclohexene) than compared to its open chained counterparts. The proportion of β-nitroalkene formed from 1-methylcyclohexene was also comparably greater than a comparable open-chain alkene. The proportion of β-nitro nitrate was not decreased by increasing the ratio of acetic anhydride [21].
Nitric acid simply dissolved in acetic anhydride is a relatively ineffective nitration agent. Rather, the formation of acetyl nitrate is key to a successful nitration. The protonated form of acetyl nitrate, (AcOHNO2)+, is the active nitrating species in the reaction. In the presence of the nitrate ion (as Et4N+ ONO2-), acetate ion (as LiOAc), or urea (CO(NH2)2) , the rate of reaction was decreased and there was an increase in the proportion of β-nitro nitrate. This retardation effect can be explained by the destruction of the nitrating species by deprotonation. However, the nitration reaction was still observed to occur (at a much slower rate) despite the destruction of the nitrating species, suggesting that acetyl nitrate can also serve as a relatively mild nitrating agent. A small addition of sulfuric acid prior to the addition of the substrate produces a profound increase in reactivity due to an increase in the concentration of (AcOHNO2)+ [21].
Nitration of aliphatic compounds can also be achieved via free radical addition. Being a free radical, nitrogen dioxide gas (NO2) can easily be added to a carbon-carbon multiple bond. Unfortunately, NO2 gas is toxic and difficult to handle. Nitrogen dioxide, however, can be generated in situ via the thermal decomposition of iron (III) nonahydrate Fe(NO3)3∙9H2O. A reagent system consisting of Fe(NO3)3∙9H2O/FeCl3 in boiling THF serves as a good reagent for the chloro-nitration of many alkenes. The use of acetonitrile as the solvent provided slightly better yields and shorter reaction times. LiCl can also be used as a chloride source and LiNO3 as a nitrate source, however, resulting in lower yields. Brominated and iodinated products can be produced in a similar fashion using carbon tetrabromide (CBr4) or lithium iodide (LiI) respectively. In some instances, a small amount of eliminated product (nitro alkene) was also formed. Addition of K2CO3or LiOH∙H2O to the reaction mixture provides a one-pot synthesis of nitroalkenes in relatively good yields [22].
Figure 4. Free radical addition of NO2 via the thermal decomposition of iron (III) nonahydrate [22].
The thermal decomposition of Fe(NO3)3∙9H2O generates NO2, which reacts with a simple alkene to give the radical intermediate (A). A chlorine atom from FeCl3 then traps the radical to form the chlorinated nitro product. The addition of base causes an elimination reaction to give the nitroalkene as a final product [22].
Conclusion
Nitro compounds can be synthesized in a variety of ways using a wide variety of nitrating reagents. Different methods exist for the regioselective nitration of certain compounds. By carefully controlling the reaction conditions and using the appropriate nitrating agent, many different species of nitrated products can be obtained from simple organic molecules. These nitrated products are of great interest in the field of organic chemistry due to its versatility as organic intermediates. The functionality of the nitro group serves an important role in converting these nitro compounds into many useful products.
Several mechanisms exist for the nitration of organic substrates. Nitrations of aromatic compounds and alkenes may be achieved via electrophilic substitution of the nitronium cation (NO2+) [3-7, 9-13, 21]. Synthesis of aliphatic nitro compounds may proceed via nucleophilic substitution of an alkyl halide with the nitrite ion (NO2-) [14-20]. Nitration may also be achieved via the free radical addition of nitrogen dioxide gas (NO2) [8, 22].
A wide variety of nitrating agents not only provides versatility in performing nitrations under different conditions, but also serves an important role in the determination of the final products. Some methods offer better regioselectivity, while others offer higher yields. Still, others offer products of higher purity or are less prone to competing side reactions. The selection of nitrating method and reagents lies in the interest of the researcher. Despite the many different syntheses of nitro compounds readily available, it is still plausible that new methods of nitration continue to be developed.
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Nitrations
Synthesis of Nitro Compounds Using Various Nitrating Agents
Nitration involves the introduction of a nitro group (NO2) into an organic compound [1]. This procedure is often performed on the electron-rich benzene molecule or other aryl compounds. However, nitrations can also be done on simple aliphatic compounds as well. While the importance of nitro compounds may often be neglected, the nitro group serves as an important precursor in a number of organic syntheses. Functionalization of the nitro group lies in the fact that it can be converted into a number of different functional groups. For example, the nitro group can easily be reduced to the corresponding amines. They can also be converted into aldehydes or ketones via the Nef reaction. Furthermore, they can serve as a precursor to oximes, hydroxylamines, and a number of other nitrogen derivatives [2]. Today, nitrations are most notably known for the production of explosives such as trinitrotoluene (TNT) and nitroguanidine [1].
Aromatic Nitration
In organic synthesis, nitrations are oftentimes performed on aromatic compounds. The nitration of benzene was among the first to be reported by Mitscherlich in 1834. He prepared nitrobenzene by treating benzene with fuming nitric acid. Not long after, in 1845, Hofmann and Dale reported on their pioneering work involving the nitration of benzene to give mono- and dinitrobenzenes; a reagent system consisting of nitric and sulfuric acids (‘mixed acid’) was employed. The nitronium ion (NO2+) is considered the active species in the system. In a typical system consisting of nitric and sulfuric acids, the overall equation is HNO3 +2H2SO4 ↔ NO2+ + H3O+ + 2HSO4- [3].
Aromatic nitration involves the electrophilic substitution of one or more nitro groups into an aromatic ring. Because the introduction of a nitro group deactivates the ring to further electrophilic substitution, dinitrations usually require much more vigorous conditions compared to its mononitration counterpart. In addition, dinitrations are usually performed on isolated mononitrated compounds rather than stepwise reactions in situ. Notably, the nitration reaction is always strongly exothermic; for the mononitration of benzene ΔH = -117 kJ/mol and for naphthalene ΔH = -209 kJ/mol [3].
Nitryl chloride, which can easily be prepared from nitric acid and chlorosulfonic acid, has also been used as a nitrating agent for some typical aromatic compounds. Its activity can be catalyzed by acids such as hydrogen fluoride, aluminum chloride, and boron fluoride. However, it was found only to be useful on aromatics of intermediate reactivity. Highly reactive aromatics (e.g. phenol, anisole, dimethylaniline, and naphthalene) are prone to oxidative degradation, while nitryl chloride was found to be an ineffective nitrating agent for deactivated aromatics (e.g. nitrobenzene, benzoic acid, and benzaldehyde) [4].
Nitronium trifluoromethanesulfonate (triflate), NO2+ CF3SO3-, derived from nitric acid and trifluoromethanesulfonic acid, was found to be an effective nitrating reagent for aromatic nitration in inert organic solvents. Furthermore, mono- or dinitration could be made to occur by altering the reaction conditions [5]. The nitronium triflate nitrating agent can also be generated in situ from tetramethylammonium nitrate and trifluoromethanesulfonic anhydride in dichloromethane. The ionic tetramethylammonium triflate salt and triflic acid byproducts can easily be removed via a simple aqueous workup. The resulting mononitrated product was obtained in high isolated yield and purity. Dinitrated products were also observed for particular electron rich aromatic substrates. While heterocyclic aromatic rings are less susceptible to electrophilic substitution, this procedure was found to be effective for nitrating heteroaromatic compounds as well. It was observed that increasing the number of equivalents of nitronium triflate can drive the reactions to completion [6].
The boron trifluoride-dinitrogen tetroxide complex has also been studied as a nitrating agent. The solid, stable complex was found to be an excellent nitrating agent for aromatic compounds. Dinitrogen tetroxide can be dissociated homolytically or heterolytically in several different ways. In the acid promoted dissociation of N2O4, BF3 cleaves N2O4 heterolytically into NO2- and NO2+. Thus, the structure of the BF3∙N2O4 complex was formulated to be (F3B <-- NO2)- (NO2)+. It was found that this reagent system favors ortho substitution relative to para substitution. However, nitrosation rather than nitration was observed to occur on some compounds. This may be due in part to the destruction of the complex owing to the basicity of the reactants. The reactant may have been basic enough to remove BF3 from the weakly basic N2O4 and prompt the base promoted dissociation of N2O4 into NO3- and NO+, the nitrosating ion. Thus, the BF3∙N2O4 complex may induce nitrosation rather than nitration in even weakly basic materials, such as aniline and some phenols [7].
Besides electrophilic substitution, nitration of aromatic compounds can also proceed via free-radical nitration. Both hydroxylation and nitration was found to occur in the reaction between pernitrous acid and a number of simple aromatic compounds. The products formed are mainly m-nitrocompounds or o- and p-hydroxy-compounds. The homolytic fission of pernitrous acid releases hydroxyl radicals which attack the aromatic compound producing a free aryl radical. Nitration then occurs due to nitrogen dioxide (NO2) reacting with the free aryl radicals present in the solution. It was found that hydroxylation occurs almost exclusively ortho and para to the original substituent, while nitration typically occurs meta to the original substituent [8].
The nitration of aromatic carbonyl compounds such as acetophenone, benzophenone, and other ketones results in mainly meta-nitro compounds as opposed to ortho- and para-nitro derivatives. This is due to the meta-directing power of the carbonyl serving as an activating group. In a kinetic study of the nitration of acetophenone with nitric acid, it was found that highly acidic nitrating systems offered a predominant ortho/meta directionality and considerable increase in meta-substitution. As the concentration of sulfuric acid was increased from 80% to 98% at 25°C, the ratio of ortho to meta products decreased from 0.37 to 0.25. This can be explained by the increasing contribution of the conjugate acid of acetophenone due to its protonation at high acidities, thereby enhancing its meta-directing power [9].
When aromatic ketones were treated with nitrogen dioxide (NO2) in the presence of ozone, an enhanced ortho to meta ratio was observed. The ring underwent easy nitration to give ortho- and meta-nitrated products in good yields with no observable attack on the alkyl portion of the ketone. In fact, nitration did not occur in the absence of ozone. Ortho-substitution is greatly enhanced under these conditions with ratios of ortho to meta nitrated products generally ranging from 1.1-3.8 to 1.0. The amount of para-substituted products was comparably lower or undetectable in some instances. It was found that the proportion of ortho-substituted products increased as the steric bulkiness of the side chain increased. This was also accompanied by an increase in para-substitution. When the number of substituted halogen atoms on the acetyl group of acetophenone was increased, the formation of products switched from predominantly ortho to predominantly meta and finally exclusively meta [10].
Iron has been used as a catalyst for the nitration of aromatic compounds using N2O5. The ferric acetylacetonate coordination complex Fe(acac)3 serves as a good catalyst to enhance the rate of nitration under milder conditions. As exemplified by the mononitration of the mildly activated compound toluene, the nitration reaction occurred readily at -100°C in the presence of iron, while an elevated temperature of 0°C was necessary for the reaction to proceed in the absence of the iron catalyst. The N2O5/Fe(acac)3 reagent system allows for the nitration to be performed under such low temperatures. This is particularly useful for the nitration of compounds containing functional groups that are themselves vulnerable to nitration. Furthermore, quantitative yields were obtained under much shorter reaction times, typically less than four minutes. The reaction conditions were also much milder as demonstrated by the nitration of benzaldehyde to form nitrobenzaldehyde without oxidation of the aldehyde group. Unfortunately, the exact structure of the active nitrating complex and mechanism of nitration is not fully understood. Attempts to isolate the complex have also been deemed unsuccessful. It was found that after filtering and washing the complex with dichloromethane, it failed to nitrate aromatic rings stoichiometrically. However, when additional amounts of N2O5 were added, the reaction proceeded normally. Interestingly, if the complex was not formed prior to the addition of the substrate, the reaction was significantly slower and mirrors that of a reaction performed in the absence of iron [11].
Cross-linked poly(4-vinylpyridine) supported sodium nitrite, [P4-Me] NO2, in the presence of KHSO4 is a useful polymer supported nitrating reagent for the nitration of aromatic compounds. While the reaction was found to be effective for activated aromatic compounds (e.g. phenol, catechol, hydroquinone, beta-naphthol, and N,N-dimethyl aniline), the reaction was unsuccessful for the nitration of less activated aromatic compounds (e.g. biphenyl, m-xylene, and toluene) [12].
A more recent method of aromatic nitration involves the use of guanidinium nitrate as the nitrating agent. Guanidinium nitrate in 85% sulfuric acid serves as a good reagent for the nitration of a number of different aromatic compounds, including those bearing activating and deactivating groups as well as anilines and heteroaromatic compounds. Guanidinium nitrate is converted into nitroguanidine in the presence of sulfuric acid, which can then be used to generate the nitronium ion. This procedure is especially useful for selective mononitrations, due to the absence of di-nitrated and poly-nitrated products. This process was also found to be regioselective. p-substituted nitro compounds were obtained regioselectively from monosubstituted aromatic substrates except toluene. The nitration of aniline and m-substituted anilines resulted in the formation of p-nitroanilines, whereas the nitration of o- and p-substituted anilines resulted in the formation of m-nitroanilines. Surprisingly, no nitration took place at the o-position [13].
Aliphatic Nitration
Aliphatic nitro compounds can be synthesized via the nucleophilic substitution reaction of alkyl halides. Primary alkyl halides can be converted into the corresponding nitro alkanes via a reaction with silver nitrite. Excellent yields were obtained for primary, straight chain alkyl bromides and iodides. However, primary alkyl chlorides were completely unreactive. Branching on the α-carbon drastically decreased the reactivity and amount of product formed, whereas branching on the β-carbon did not seem to affect the yields much. Secondary halides are expected to produce yields of approximately 15% and tertiary halides only 0 to 5% [14]. Milder conditions performed at room temperature using four equivalents of silver nitrite under aqueous medium have also been found to be effective for the production of primary nitroalkanes from primary alkyl halides. The use of four equivalents of silver nitrate creates the necessary conditions to minimize the formation of the corresponding alcohol. This method works well on alkyl bromides and alkyl iodides, while preserving other functionalities under these milder conditions. The formation of alkyl nitrites as byproducts is also greatly reduced. Unfortunately, this method was found to be ineffective on secondary halo derivatives [15].
Nitroalkanes can be produced via the nitration of alkyl halides with metal nitrites. In the Victor-Meyer reaction, silver nitrite in diethyl ether is employed [16], while in the Kornblum reaction, sodium nitrite in N,N-dimethylformamide (DMF) [17] or dimethyl sulfoxide (DMSO) [18] is used. A slightly modified version of the Victor-Meyer reaction provided primary nitroalkanes of high purity in good yields. Lower reaction temperatures (45-55°C) were employed, as well as the use of petroleum ether as the solvent [16]. The main advantage of the Kornblum reaction over the Victor-Meyer reaction is its effectiveness on secondary halides. The use of DMF greatly enhances the solubility of sodium nitrite. Addition of a small amount of urea to DMF further enhances the solubility of sodium nitrite, making it an effective nitrating agent for even secondary alkyl halides and halogenated cyclic hydrocarbons. The reaction of alkali nitrites with alkyl halides is also appreciably faster in this medium, which minimizes the formation of competing side products. While alkyl iodides and alkyl bromides are useful in the synthesis of nitroalkanes, alkyl chlorides react too slowly to be useful [17]. DMSO proves to be an even better solvent for the nitration reaction due to the higher solubility of sodium nitrite in DMSO than DMF. This presents the possibility of more concentrated mixtures and effectively shorter reaction times. However, open chain secondary alkyl bromides seemed to give slightly higher yields in DMF. The two solvents also provided approximately the same yields for secondary alkyl iodides [18].
Dinitrogen pentoxide (N2O5) can be used as a nitrating reagent for the conversion of an amine to the corresponding nitramine. It has been found to be effective on a number of aromatic amines as well as secondary aliphatic amines. However, this reagent system was ineffective for primary amines, as N2O5 causes the acid-catalyzed decomposition of primary nitramines [19]. Nitrogen tetroxide (N2O4) has also been studied as a nitrating agent. It was found that nitrogen tetroxide can react either as a nitrosating agent or as a nitrating agent. Nitrosation was prevalent under most conditions, while nitration was found to occur only at low temperatures and only with reactants that are strong bases [20].
This is due to the equilibrium that is established between the two isomeric forms of nitrogen tetroxide. The displacement of the nitrite ion from I leads to nitration, while the displacement of the nitrate ion from II leads to nitrosation [20].
Acetyl nitrate serves as a rapid and effective nitrating agent for many alkenes. This nitrating agent is easily obtained from the reaction of 70% nitric acid with excess acetic anhydride. While nitric acid in acetic acid has also been used as a nitrating agent, nitric acid in acetic anhydride has been shown to be a much more effective nitrating agent. Alkenes typically undergo an addition reaction withAcO-NO2 in a Markovnikov orientation to form β-nitro acetates. Smaller amounts of β-nitroalkenes and β-nitro nitrates are also obtained. The β-nitro acetates can be easily separated from the higher boiling β-nitroalkenes and β-nitro nitrates via distillation. RCH2CH2CH=CH2 (e.g. 1-butene) and R2CHCH2CH=CH2 (e.g. 3-methyl-1-butene) type alkenes were found to be relatively unreactive, producing low yields of β-nitro nitrates and β-nitro acetates in approximately equal proportions. A small amount of sulfuric acid was found to be remarkably effective at promoting the nitration of otherwise unreactive alkenes, such as 2-chloro-2-methylpropene. Overall yields were found to increase as the ratio of nitrating agent to alkene was increased from 1 to 2. This shows that the amount of nitrating agent is less than the moles of nitric acid used. Time and temperature did not seem to appreciably affect the total yield or ratio of products. Most of the reactions were essentially “complete” within five minutes. The proportion of β-nitro nitrate product was much greater for cyclic hydrocarbon compounds, (e.g. cyclopentene and cyclohexene) than compared to its open chained counterparts. The proportion of β-nitroalkene formed from 1-methylcyclohexene was also comparably greater than a comparable open-chain alkene. The proportion of β-nitro nitrate was not decreased by increasing the ratio of acetic anhydride [21].
Nitric acid simply dissolved in acetic anhydride is a relatively ineffective nitration agent. Rather, the formation of acetyl nitrate is key to a successful nitration. The protonated form of acetyl nitrate, (AcOHNO2)+, is the active nitrating species in the reaction. In the presence of the nitrate ion (as Et4N+ ONO2-), acetate ion (as LiOAc), or urea (CO(NH2)2) , the rate of reaction was decreased and there was an increase in the proportion of β-nitro nitrate. This retardation effect can be explained by the destruction of the nitrating species by deprotonation. However, the nitration reaction was still observed to occur (at a much slower rate) despite the destruction of the nitrating species, suggesting that acetyl nitrate can also serve as a relatively mild nitrating agent. A small addition of sulfuric acid prior to the addition of the substrate produces a profound increase in reactivity due to an increase in the concentration of (AcOHNO2)+ [21].
Nitration of aliphatic compounds can also be achieved via free radical addition. Being a free radical, nitrogen dioxide gas (NO2) can easily be added to a carbon-carbon multiple bond. Unfortunately, NO2 gas is toxic and difficult to handle. Nitrogen dioxide, however, can be generated in situ via the thermal decomposition of iron (III) nonahydrate Fe(NO3)3∙9H2O. A reagent system consisting of Fe(NO3)3∙9H2O/FeCl3 in boiling THF serves as a good reagent for the chloro-nitration of many alkenes. The use of acetonitrile as the solvent provided slightly better yields and shorter reaction times. LiCl can also be used as a chloride source and LiNO3 as a nitrate source, however, resulting in lower yields. Brominated and iodinated products can be produced in a similar fashion using carbon tetrabromide (CBr4) or lithium iodide (LiI) respectively. In some instances, a small amount of eliminated product (nitro alkene) was also formed. Addition of K2CO3or LiOH∙H2O to the reaction mixture provides a one-pot synthesis of nitroalkenes in relatively good yields [22].
The thermal decomposition of Fe(NO3)3∙9H2O generates NO2, which reacts with a simple alkene to give the radical intermediate (A). A chlorine atom from FeCl3 then traps the radical to form the chlorinated nitro product. The addition of base causes an elimination reaction to give the nitroalkene as a final product [22].
Conclusion
Nitro compounds can be synthesized in a variety of ways using a wide variety of nitrating reagents. Different methods exist for the regioselective nitration of certain compounds. By carefully controlling the reaction conditions and using the appropriate nitrating agent, many different species of nitrated products can be obtained from simple organic molecules. These nitrated products are of great interest in the field of organic chemistry due to its versatility as organic intermediates. The functionality of the nitro group serves an important role in converting these nitro compounds into many useful products.
Several mechanisms exist for the nitration of organic substrates. Nitrations of aromatic compounds and alkenes may be achieved via electrophilic substitution of the nitronium cation (NO2+) [3-7, 9-13, 21]. Synthesis of aliphatic nitro compounds may proceed via nucleophilic substitution of an alkyl halide with the nitrite ion (NO2-) [14-20]. Nitration may also be achieved via the free radical addition of nitrogen dioxide gas (NO2) [8, 22].
A wide variety of nitrating agents not only provides versatility in performing nitrations under different conditions, but also serves an important role in the determination of the final products. Some methods offer better regioselectivity, while others offer higher yields. Still, others offer products of higher purity or are less prone to competing side reactions. The selection of nitrating method and reagents lies in the interest of the researcher. Despite the many different syntheses of nitro compounds readily available, it is still plausible that new methods of nitration continue to be developed.
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